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News & Analysis24 Scientific American June 2000

VANCOUVER—Edith G. and Pat-rick L. McGeer are in their70s, and after 15 years of re-search and 670 autopsied

brains, they know only too well the oddsof developing Alzheimer’s. About 10 per-cent of those older than 65—and nearlyhalf of those older than 85—have the dis-ease. But they also know exactly whatthey’ll do if, or even before, the diseasestrikes. They’ll take the kind of drugs mil-lions rely on to relieve their headachesand joint pain—drugs in the same class asibuprofen and aspirin. The McGeers, hus-band-and-wife neuroscientists at the Uni-versity of British Columbia, arebetting on nonsteroidal anti-in-flammatories as the first way toslow Alzheimer’s.

Alzheimer’s researchers havehad anti-inflammatory agentson their radar screen since at leastthe early 1990s, when the Mc-Geers and their colleague JosephRogers of Sun Health Research In-stitute in Sun City, Ariz., noticeda startlingly low occurrence ofAlzheimer’s in arthritics. Morethan 20 follow-up studies madethe link to anti-inflammatories.No one knows exactly why thatlink exists—the ultimate cause ofAlzheimer’s itself is still foggy—but the McGeers believe it is relat-ed to the growing but still un-proved theory that the diseasecan best be described as the brain’s ownimmune system turning on it.

The characteristic plaques and tanglesfound in the brains of Alzheimer’s suffer-ers are filled with compounds, especiallythe protein beta-amyloid, that can kick-start the brain’s innate immune system.Ancient and primitive, isolated from therest of the body, the brain’s immune sys-tem can be “ferociously active,” EdithMcGeer says. Its primary workers are mi-croglial cells, the brain’s equivalent ofmacrophages, which engulf and degradeintruding debris. In Alzheimer’s brains,the plaques and tangles are marked formicroglial destruction with the proper

protein tags, but then something goeshaywire. The microglial cells begin pro-ducing toxins that kill off good cells alongwith the bad. That further provokes thebrain’s inflammatory response, which killsmore neuronal cells, setting up a viciouscycle. Once the damage has been done,nothing can reverse it. “What the brain isdoing is mistaking friend for foe,” PatrickMcGeer explains.

The process can be described as inflam-matory even though the brain doesn’tswell or become painful like an inflamedjoint. If the brain had pain receptors, Alz-heimer’s would undoubtedly hurt—and

be detected much earlier. As it is, plaquesand tangles may start forming 20 or 30years before any symptoms begin to show.

The only drugs now approved for treat-ment of Alzheimer’s in Canada and theU.S.—tacrine (sold under the name Cog-nex) and donepezil (sold as Aricept)—tem-porarily boost memory, often by inhibit-ing cholinesterase, an enzyme that breaksdown neurotransmitters. They don’t ad-dress the cycle of neuronal cell destruc-tion—but anti-inflammatories might.

“If you can decrease the amount of inflammation, it should decrease theamount of damage,” reasons Bill Thies ofthe Alzheimer’s Association, based in

Chicago. And that in turn should slow theonset of dementia. “If you can slow theprogression . . . past the point of death,”Thies notes, “then you’ve effectively end-ed the disease.”

The McGeers have concentrated theirwork on dapsone, an anti-inflammatoryused for decades to treat leprosy. In a1992 study in Japan of 3,782 leprosy pa-tients, the prevalence of dementia was 2.9percent in those continuously treatedwith dapsone or a closely related drug(promine), compared with 6.25 percentin the untreated group. When the treatedpatients were taken off the drug, the inci-

dence of Alzheimer’s shot up. Inthe second half of this year,through the Vancouver-basedcompany Immune Network Re-search, dapsone is going straightto a phase II clinical trial for usewith Alzheimer’s. (It needs nophase I approval, which deter-mines drug safety, because it isalready approved for leprosy.)

Dapsone joins a range of otheranti-inflammatories that are un-der trial or investigation for Alz-heimer’s treatment. Merck andMonsanto have their own, so-called COX-2 inhibitors namedVioxx (rofecoxib) and Celebrex,which are in phase III trials thisyear; both are already sold totreat arthritis. And the NationalInstitute on Aging launched a 14-

month trial in February with rofecoxib andnaproxen. The McGeers suspect the bestsolution will be a combination of drugs,and dapsone can be added to that list.

Both dapsone and the COX-2 inhibitorsseem free of the major side effect thatplagues many anti-inflammatories—mildgastrointestinal bleeding and stomachpains. But even anti-inflammatories thatcarry that small risk seem well worth itwhen compared with the devastation ofAlzheimer’s. Says Patrick McGeer: “I’lltake brains ahead of guts.” —Nicola Jones

NICOLA JONES is a freelance writer basedin Vancouver, B.C.

Soothing the Inflamed BrainAnti-inflammatories may be the first drugs to halt the progression of Alzheimer’s

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HUSBAND-AND-WIFE research team of Patrick and Edith

McGeer has high hopes for dapsone, a leprosy drug.

Copyright 2000 Scientific American, Inc.